The marine environment provides a plenitude of naturally produced organic pollutants and toxins. Of these, polybrominated marine natural products, such as endocrine disrupting polybrominated diphenyl ethers, dioxins, and pyrroles, biomagnify in the marine food web and are available to be passed onto humans via seafood. Additionally, naturally produced volatile polybromomethanes are extremely potent ozone damaging agents. Despite their recognized toxic potential and detrimental environmental impact, routes for the production of these polybrominated molecules in the marine metabolome have not been elucidated. This in turn hinders the development of tools to discover and query the biosynthetic potential of other natural sources that introduce these polybrominated pollutants into the environment. The research strategy outlined in this application takes a fresh look at these molecules from a biochemists' perspective, and uses an interdisciplinary metagenome mining approach to characterize the biosynthetic routes of polybrominated pollutants and toxins. The ecological and human health implications of the study design are substantiated by the emphasis that is laid on investigating marine invertebrates and algae that are exceptionally prolific natural producers of these molecules. Compelling preliminary data is provided to support the biosynthetic hypotheses that are advanced in this proposal and a combination of genetic and biochemical experiments are proposed to rigorously test these hypotheses. Complemented by mass spectrometry based analytical investigations, data generated during the course of this study will be used to drive the discovery of underappreciated additional natural sources that are contributing to the human and environmental exposure to these naturally produced polybrominated pollutants. Furthermore, the research design recognizes and seeks to exploit the numerous opportunities that will present themselves for the advancement of halogenation enzymology and novel marine biochemistry. Overall, the research design fosters the development of a creative, independent research program that will be competitive for subsequent independent funding and that will help advance the mission of the NIH. The application is designed to supplement Dr. Agarwal's prior research experience and to provide him with substantive technical and intellectual training during the mentored phase to transition to an independent, tenure-track position. Dr. Agarwal's primary mentor, Dr. Moore, and co-mentor, Dr. Allen, are carefully chosen for their diverse and complementary scientific expertise to cover all elements of the proposed research. Furthermore, Dr. Agarwal has assembled a team of three collaborators to provide specific scientific contributions, and a three member Scientific Advisory Committee to oversee and advise on his scientific progression and career development. All mentors, collaborators, and advisors are senior scientists and have extensive experience in advising postdoctoral scientists as they transition to an independent academic career.